Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer
Open Access
- 22 July 2013
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 110 (32), 13091-13096
- https://doi.org/10.1073/pnas.1302507110
Abstract
The receptor tyrosine kinases Axl and Mer, belonging to the Tyro3, Axl and Mer (TAM) receptor family, are expressed in a number of tumor cells and have well-characterized oncogenic roles. The therapeutic targeting of these kinases is considered an anticancer strategy, and various inhibitors are currently under development. At the same time, Axl and Mer are expressed in dendritic cells and macrophages and have an essential function in limiting inflammation. Inflammation is an enabling characteristic of multiple cancer hallmarks. These contrasting oncogenic and anti-inflammatory functions of Axl and Mer posit a potential paradox in terms of anticancer therapy. Here we demonstrate that azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced inflammation-associated cancer is exacerbated in mice lacking Axl and Mer. Ablation of Axl and Mer signaling is associated with increased production of proinflammatory cytokines and failure to clear apoptotic neutrophils in the intestinal lamina propria, thereby favoring a tumor-promoting environment. Interestingly, loss of these genes in the hematopoietic compartment is not associated with increased colitis. Axl and Mer are expressed in radioresistant intestinal macrophages, and the loss of these genes is associated with an increased inflammatory signature in this compartment. Our results raise the possibility of potential adverse effects of systemic anticancer therapies with Axl and Mer inhibitors, and underscore the importance of understanding their tissue and cell type-specific functions in cancer.Keywords
This publication has 50 references indexed in Scilit:
- Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancerNature Genetics, 2012
- Design, Synthesis, and Biological Evaluation of a Series of Novel AXL Kinase InhibitorsACS Medicinal Chemistry Letters, 2011
- Hallmarks of Cancer: The Next GenerationCell, 2011
- TAM receptor signaling and autoimmune diseaseCurrent Opinion in Immunology, 2010
- Inflammation and oncogenesis: a vicious connectionCurrent Opinion in Genetics & Development, 2009
- A protective function for interleukin 17A in T cell–mediated intestinal inflammationNature Immunology, 2009
- IL-6 and Stat3 Are Required for Survival of Intestinal Epithelial Cells and Development of Colitis-Associated CancerCancer Cell, 2009
- Immunobiology of the TAM receptorsNature Reviews Immunology, 2008
- TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human CancerAdvances in Cancer Research, 2008
- Chemically induced mouse models of intestinal inflammationNature Protocols, 2007